microRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3' UTR. We show that the near-perfect miRNA site selectively triggers miR-29b destabilization through 3' trimming and restricts its spatial expression in the cerebellum. Genetic disruption of the miR-29 site within mouse Nrep results in ectopic expression of cerebellar miR-29b and impaired coordination and motor learning. Thus, we demonstrate an endogenous target-RNA-directed miRNA degradation event and its requirement for animal behavior.

GeneCore for preparation of the Methyl-seq libraries. Author contributionsA.Z. contributed to the design, execution and analysis of most experiments. T.A. helped established the IP conditions and performed the mass-spectrometry analysis under the guidance of J.R. and R.C.A. R.B. and Y.K. performed the bioinformatic analysis of the Methyl-seq data or sRNA-seq as well as RNA-seq data, respectively. T.S. prepared the sRNA-seq libraries and together with Y.K. the RNA-seq libraries of P20 testes. M.H and A.C. performed the homology alignment of the SPOC and TFIIS-M domains. L.V. performed the IF staining of HA-MIWI2 and generated the gonocytes microarray dataset. Y.R.P. performed the phylogenetic analysis under guidance of A.S. D.O'C. conceived and supervised this study. D.O'C. and A.Z wrote the final version of the manuscript.